The goal of this research is the invention, synthesis, and evaluation of conformationally constrained mimics of peptide secondary structure. The first generation of rigid dipeptide mimics that will be investigated is based upon 1,2,3-trisubstituted cyclopropanes as designated by the general term -Xaa psi[CP]Yaa-. The backbone substituents in these replacements may be disposed in either a cis or trans relationship on the cyclopropane ring, thereby locking the peptide backbone in either an extended beta- strand conformation or a beta-turn motif by constraining the phi or the psi angles, respectively. The chi1-angles are also restricted to direct the amino acid side chains in specific orientations corresponding approximately to the gauche(-), gauche(+), and anti (+ or - 80) conformations. New methods for the asymmetric synthesis of functionalized, trisubstituted cyclopropanes will be developed, and novel tactics will be invented that will facilitate their incorporation into pseudopeptides. The conformational effects of introducing extended and turned -Xaa psi(CP]Yaa,- mimics into peptides will be analyzed by modeling, NMR and X- ray studies. Cis -Xaa psi[CP]Yaa- isosteres will be substituted into analogues of oligopeptides that are known to adopt beta-turns in solution and/or in the solid state for comparative structural studies. X-Ray studies of inhibitors complexed with HIV-1 protease and stromelysin will be conducted in collaborations with Dr. John Erickson (NCI) and Dr. Jens Birkoft (Hoffmann LaRoche), respectively. The efficacy of these new replacements will be evaluated by incorporating them into derivatives of biologically active peptides and comparing their affinities with those of the parent ligands for the same enzyme active sites and receptors. Pseudopeptides that contain trans -Xaa psi[CP]Yaa- replacements to enforce a local a-strand structure will be tested as inhibitors of HIV-1 protease (AIDS), type IV collagenase (rheumatoid arthritis and cancer metastasis), and stromelysin. The enkephalins appear to bind to opioid receptors via a beta-turn, so cis -Xaa psi[CP]Yaa- subunits will be incorporated into enkephalin analogues to assess their ability to mimic the biologically active conformation of these neuropeptides. The tetrapeptide Cys-Val-Phe-Met (CVFM) seems to adopt a type I beta-turn when bound to farnesyltransferase, so the potential of cis -Xaa psi[CP]Yaa- replacements to mimic the biologically active conformation of CVFM analogues will also be investigated. Potential HIV-1 protease inhibitors will be assayed at Abbott Laboratories, and inhibitors of the matrix metalloproteinases collagenase and stromelysin will be evaluated at Procter & Gamble. Enkephalin analogues will be submitted to the NIDA for assays for opiate receptor affinity and functional activity profiles, and the CVFM analogues will be tested by Dr. James Marsters at Genentech.